Browsing by Subject "humans"

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Influence of Thermoregulatory and Nonthermoregulatory Control Mechanisms of Arterial Blood Pressure During Recivert from Exercise in Humans
(2001-05-10) Carter, Robert; Michael L. Smith; Robert L. Kaman; Thomas Yorio
Carter, III Robert, Thermoregulatory and nonthermoregulatory control of arterial pressure during recovery from exercise in humans. Doctor of Philosophy (Biomedical Sciences). May 2001; 153p; 4 tables, 17 figures; 100 titles. The mechanisms of arterial blood pressure control during exercise is well established; however, much less is known about the regulation of arterial blood pressure immediately after intense or prolonged dynamic exercise. Inactive recovery from dynamic exercise is associated with cessation of the primary exercise stimuli from the brain (central command), Skeletal muscle pumping, which contributes to increases in venous return during exercise is also stopped during inactive recovery from exercise. Thus, the skeletal muscle pump and central command each contribute importantly to elevation and maintenance of arterial blood pressure regulation and cerebral blood flow during exercise. When exercise is intense and/or prolonged, the resulting thermal load exacerbates the challenge to maintain arterial blood pressure and cerebral blood flow both during exercise and particularly during recovery from exercise and thereby increases the risk of syncope. Recently, we found that the skeletal muscle pump plays a major role in arterial blood pressure control during recovery from brief (3 min), mild (60% of maximal HR) exercise in which there was no thermal load. However, how the mechanisms of arterial pressure regulation operate during recovery from intense or prolonged exercise when a thermal load occurs is unknown. Therefore, the purpose of the investigations described herein, was to quantify the mechanisms of the carotid baroreflex function, central command, and the skeletal muscle pump when a thermal stress occurs on arterial blood pressure regulation during recovery from exercise in humans. In addition, differences in arterial blood pressure regulation in women and men during recovery from exercise were addressed in women and men. To investigate these mechanisms, we investigated the carotid-cardiac baroreflex function, cardiovascular, and thermoregulatory responses in volunteer subjects during inactive and active recovery from prolonged exercise improved the function of the baroreflex by increasing the functional reserve of the reflex to buffer against hypotensive stimuli. Our data also suggest that thermoregulatory factors contribute to decreases in MAP after inactive recovery from exercise. In addition, the metabolic state of skeletal muscle during longer duration exercise (15 min) may contribute to these responses during inactive recovery from exercise. These results support the hypothesis that thermal stress contributes to the rapid decreases in arterial blood pressure during inactive recovery following dynamic exercise. To investigate gender differences in arterial pressure regulation during recovery from exercise, we compared 11 women and 8 men during 3 min of exercise and 5 min of inactive and active recovery from exercise. Interestingly, at 1 minute after exercise, MAP decreased less during inactive recovery in men when compared to women. This difference was due to greater decreases in SV and less increase in TPR during inactive recovery from exercise in women compared to men. MAP decreased less during active recovery in men when compared to women. These findings suggest that women may have increased risk of post-exercise orthostatic hypotension and that active recovery from exercise may reduce this risk.
Investigation of Proteasome Chymotryptic Activities and Effects on their Inhibition in Rat and Human Natural Killer Cells
(2003-04-01) Lu, Min; Goldfarb, Ronald H.; Borejdo, Julian; Easom, Richard
Lu, Min, Investigation of Proteasome Chymotryptic Activites and Effects of Their Inhibition in Rat and Human Natural Killer Cells. Doctor of Philosophy (Biochemistry and Molecular Biology), April, 2003, 185 pp., 3 tables, 32 illustrations, bibliography, 158 titles. The proteasome is a multicatalytic proteinase complex that is involved in the major extralysosomal pathway responsible for intracellular protein degradation in mammalian cells. This dissertation focuses on investigating proteasome chymotryptic activities and the effects of selective inhibitors of these activities on the function of natural killer (NK) cells. In this dissertation, 20S proteasomes derived from rat RNK16 cells were purified and some of their biochemical and biophysical properties were investigated extensively. The results indicated that RNK16 cell-derived proteasome differ from the proteasome of other origins in many aspects including substrate selectivity, inhibitor specificity, and kinetic regulation, although they may share some common biochemical properties with others. To investigate the effects of proteasomal inhibition on the function of NK cells, several proteasome inhibitors were used including MG115, MG132, clasto-lactacystin-β-lactone, EGCG and LLnL. MG115 and MG 132 were shown to induce apoptosis of RNK16 cells, as evidenced by DNA fragmentation, caspase-3 activation and the appearance of sub-G1 cell populations. Activation of multiple caspases and increased expression of cell surface Fas (CD95) protein were also observed following the treatment of RNK16 cells by these two inhibitors. This dissertation also tested the hypothesis that different cell types could respond differentially to proteasome inhibitors. The effects of several proteasome inhibitors were determined on the purified 20S proteasomal and 26S proteasomal chymotrypsin-like activity in whole cell extracts and intact YT and Jurkat cells, human NK and T cell lines respectively. Following such treatment, caspase-3 activation occurred much earlier in Jurkat cells than YT cells; cell cycle analysis indicated a sub-G1 apoptotic cell population in Jurkat cells and G2/M arrest in YT cells. In addition, accumulation of p27 and IκB-α was detected only in Jurkat cells, but not YT cells. Therefore, proteasome inhibitors appear to act differentially in cell cycle progression and apoptosis signaling pathways between human NK and T cells. These studies indicate that the generation of ideal proteasome inhibitors for the treatment of malignancies could be screened or designed to specifically induce cancer cells to undergo programmed cell death, while having little or no apoptosis-inducing abilities for natural killer cells and other cells of the immune response, thus enhancing the selectivity and specificity of the anti-cancer, apoptosis-inducing capabilities of proteasome inhibitors.
Mechanisms of Post-Apneic Symathoinhibition in Humans
(2002-08-01) Swift, Nicolette Muenter; Smith, Michael; Barker, David; Burk, John R.
Muenter Swift, Nicolette, Mechanisms of Post-Apneic Sympathoinhibition in Humans. Doctor of Philosophy (Biomedical Sciences), August, 2002, 110 pp., 14 figures, references. Apnea is accompanied by a concomitant rise in arterial pressure and muscle sympathetic nerve activity (MSNA), the latter primarily due to chemoreflex stimulation and possibly the lack of sympathoinhibitory input from pulmonary stretch receptors. The progressive sympathoexcitation during apnea suggests a possible overriding of arterial baroreflex sympathoinhibitory input to sympathoregulatory centers by apnea-induced sympathoexcitatory mechanisms. Nevertheless, it is unknown whether apnea attenuates baroreflex control of MSNA. Apnea termination is accompanied by a profound and immediate sympathoinhibition, the mechanisms of which are unclear; however, potential mediators include normalization of blood gases (i.e. chemoreflex unloading), the lung inflation reflex, and arterial baroreflex stimulation. Therefore, the purpose of the current studies was to: i) determine the contribution of chemoreflex unloading to post-apneic sympathoinhibition, ii) determine the contribution of the lung inflation reflex to post-apneic sympathoinhibition, and iii) determine whether carotid baroreflex control of MSNA is altered by apnea and its termination. The first study compared MSNA during post-apneic administration of room air versus a gas mixture designed to maintain the subjects’ end-apneic alveolar gas levels. Regardless of post-apneic gas administration, post-apneic MSNA was at or below baseline pre-apneic levels; thus; chemoreflex unloading does not contribute to post-apneic sympathoinhibition. Furthermore, quantification of post-apneic MSNA associated only with the low lung volume phase of respiration, when sympathoinhibitory input from the lung inflation reflex is minimal, demonstrated that post-apneic sympathoinhibition persists even during the low lung volume phase of respiration, when sympathoinhibitory input from the lung inflation reflex is minimal, demonstrated that post-apneic sympathoinhibition persists even during the low lung volume phase of respiration. Therefore, the lung inflation reflex does not appear to be the primary mediator of post-apneic sympathoinhibition. The second study utilized neck suction (NS) and neck pressure (NP) to assess carotid baroreflex function during and following sleep apnea. The sympathoinhibitory response to -60 Torr NS was maintained throughout apnea; conversely, the sympathoexcitatory response to +30 Torr NP was attenuated for nearly one minute post-apnea. Thus, carotid baroreflex control of MSNA is not altered by apnea but is transiently attenuated by apnea termination. We propose that the carotid baroreflex-MSNA function curve resets rightward and upward during apnea. Return of the function curve to baseline upon apnea termination may partly explain the reduced MSNA response to NP post-apnea.
The Effects of Short-Term Intermittent Hypoxic Apneas on Sympathetic Nerve Activity and the Chemoreflex Control of Sympathetic Nerve Activity in Humans
(2004-05-01) Cutler, Michael J.; Smith, Michael L.; Raven, Peter B.; Downey, H. Fred
Cutler, Michael J., The Effects of Short-Term Intermittent Hypoxic Apneas on Sympathetic Nerve Activity and the Chemorelex Control of Sympathetic Nerve Activity in Humans. Doctor of Philosophy (Integrative Physiology), May 2004. Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA both of which likely play an important role in the development of hypertension in these patients. Hypoxia is postulated to be primary stimulus for elevated daytime MSNA and altered chemoreflex control of MSNA both of which likely play an important role in the development of hypertension in these patients. Hypoxia is postulated to be the primary stimulus for elevated daytime MSNA and altered chemoreflex control of MSNA in OSA patients. Recently, short-term exposure to hypoxia was shown to produce sustained elevation of MSNA. Therefore, we studied the effects of 20 min of intermittent voluntary hypoxic apneas (to mimic OSA) on MSNA and the chemoreflex control of MSNA during 180 min post exposure. Also, we compared MSNA and chemoreflex control of MSNA for 180 min following either 20 min of intermittent voluntary hypoxic apneas, hypercapnic hypoxia, or isocapnic hypoxia. Consistent with our hypotheses, both total MSNA and MSNA burst frequency were elevated following 20 min of intermittent hypoxic apnea compared to baseline (p [less than] 0.05). Both total MSNA and MSNA burst frequency remained elevated throughout the 180 min recovery period and were statistically different from time control subjects throughout this period (p [less than] 0.05). Additionally, a significant main effect for chemoreflex control of SNA was observed following 20 min of intermittent hypoxic apneas (p [less than] 0.001). Specifically, the MSNA response to a single hypoxic apnea was attenuated 1 min post exposure compared to baseline (p [less than] 0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (p [less than] 0.05). Finally, comparison of treatment groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia) revealed no differences in resting MSNA (p=0.50) and the chemoreflex control of MSNA (p=0.69) during recovery. Therefore, these data support the hypothesis that short-term exposure to intermittent hypoxic apneas resulted in sustained elevation of MSNA and altered chemoreflex control of MSNA. Furthermore, these responses appear to be mediated by hypoxia.